PROJECT SUMMARY Sepsis affects millions of Americans annually and is a leading cause for intensive care utilization. Currently no therapies exist to target the abnormal host response that is widely acknowledged to contribute to multi-organ dysfunction and death from severe infection. The applicant has received continuous R01 support from the NHLBI since 2007-2008 to research the host vascular response in sepsis. Our group has identified the Tie2 receptor and its ligands, the Angiopoietins, as an important switch in the endothelium that may govern essential elements of the vascular response to sepsis. We have proposed that Angiopoietin-2, an antagonist of Tie2 that is induced during sepsis, potentiates vascular leakage and thereby contributes to acute respiratory distress arising from sepsis and related conditions. Since Angiopoietin-2 can be measured peripherally, we have also proposed that its circulating concentration may predict the risk of adverse outcomes from sepsis and may enable clinicians to track the host vascular response in a quantitative and operator-independent fashion. Finally, we have recently found evidence that polymorphisms at the TIE2 locus itself may inform the level of gene expression, and in turn, how well or poorly an individual's blood vessels respond to the stress of sepsis. This body of work to which we and many others have now contributed suggests that we are on the cusp of developing breakthrough personalized medicine approaches based on the host vascular response in sepsis. Such advances could revolutionize the care delivered in our ICUs. This application seeks to develop the core hypothesis that the Tie2 axis may be a crucial determinant of the host vascular response in sepsis through the following three themes: (1) create humanized mouse models of the Tie2 axis using cutting-edge genome engineering to model the human host vascular response, and its genetic determinants, in a physiological context; (2) identify major mechanisms by which Tie2 and the endothelium regulate hemostasis in sepsis; and (3) study the crosstalk between the microcirculation and metabolically active organs to understand how the host vascular response and dysmetabolism collaborate to drive multi-organ dysfunction. The outstanding qualifications of our team in the Tie2 field, genetic epidemiology, thrombosis research, and metabolism uniquely position us to deliver an unprecedented and integrated molecular view of sepsis from the perspective of blood vessels that is not only highly responsive to the challenges in sepsis research identified by global leaders, but could fundamentally alter paradigms of patient care in the ICU.